KR950005866B1 - 쇽 Therapeutic drugs that block EDRF efficacy or its production - Google Patents

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Description

쇽 Therapeutic drugs that block EDRF efficacy or its production

The present invention relates to a novel drug for the treatment of various shocks, such as stress, septic shock or cosmetological shock by inhibiting relaxation phosphorus (EDRF) induced by endothelin.

Despite the use of large quantities of certain antibiotics and careful monitoring of the surgery, sepsis and endotoxemia are still the leading cause of death in very fine medical care. In patients with poor survival, peripheral blood vessels tend to have low resistance, which is called unrelenting hypotension. In fact, patients die more often due to peripheral vascular insufficiency than cardiac insufficiency, especially since they cause severe vasodilation in the preliminary stage. In addition, persistent vasodilation in these patients responds only momentarily by infusion of catecholamines (or other vasoconstrictor agonists) and, therefore, usually cannot be recovered due to vascular hyporesponsiveness. The hyporeactivity of these vessels is the leading cause of death.

FIELD OF THE INVENTION The present invention relates to treating low response of blood vessels in various shock conditions, such as sepsis, endogenous poisoning and other diseases that cause persistent and intense systemic vasodilation. Such treatment includes administering an effective amount of an agent that blocks the efficacy or production of endothelin-induced relaxation factor (EDRF) or nitric oxide, and similar factors.

We describe L-arginine such as LN-monomethyl arginine (ie, N-NMMA), L-iminoethylornithine (ie, L-NIO), and L-nitroarginine methyl ester (ie, L-NAME). Drugs that block the efficacy or production of EDRF, such as derivatives, have been found to restore the reduced responsiveness to catecholamines, effectively inhibiting the hyporeactivity of blood vessels.

As the above-mentioned derivatives, there are L-isomers of the compound represented by the following formula.

Wherein R ₁ and R ₄ are H, CH ₃ or C ₂ H ₅ , R ₂ is H or NO ₂ , and R ₃ is NHR ₄ , CH ₃ or C ₂ H ₅ .

Accordingly, the present invention relates to therapeutic compositions in which an effective amount of at least one such compound is mixed with any carrier and / or diluent suitable for injection administration.

Examples of techniques in this field can be found in European Patent Application No. 86117895.2 (filed Dec. 22, 1986), which describes cell protective agents, (D) citing N-methylarginine and have. However, it should be noted that, firstly, this compound does not have all the activities included in the scope of the present invention, and secondly, the compound of the present invention does not have a cell protective action.

In the case of demonstration by experiment, it is already known from the evidence that the experiments using animal models in vivo and in vitro are very similar to the low response of human blood vessels to neurotransmitters or hormones causing blood pressure rise ( See: Sepsis and septic shock.A Review of laboratory models and a proposal.J by Witterman KA, Baue AE and Chaudry TH. of Surgical Res.Vol. 29, pp. 189-201 (1980), by Parat J. Alteration invascular reactivity in sepsis and endotoxemia.In: Edited by Vincent J.L. intensive care and emergency medicine.Springer Vol. 8, 299-308 (1989). The effects of these abnormal vascular responses and EDRF blockers can be demonstrated in vascular tissues isolated from the animal in the bovine state.

In the case of the compounds of the present invention, the above was demonstrated by the following experiment.

Sprague Dolay rats (weight: 220-330 g) were injected with E. coli endogenous toxin (0114B4 Sigma) intraperitoneally at 10 mg / kg. After 3 hours, the cervix of the rat was dislocated and lethal, and the thoracic aorta was removed from the surrounding tissue. A 2 mm wide cyclic sample was suspended in an organ bath containing 10 ml of Krebs Henseleit physiological solution at 37 ° C. under a tension of 2 g and supplied with 95% O ₂ /5% CO ₂ gas. The shrinkage response was measured using a force displacement transducer (Auguet M., Millaflotte S., PE Chabrier, P. Bracher). Comparative effects of endotelin and phorbol 12-13 dibutyratein rat arota.Life Sci.Vol. 45, 21, pp. 2051-2059 (1989).

In some experiments, the endothelium ruptured slowly (-E). Phenylephrine (PE) in cyclic control samples from animals administered with endothelial (+ E) saline solution (0.9% NaCl) or without endothelial (E-) saline solution (0.9% NaC1) The contraction caused by was stable during that period. Arginine derivatives (at concentrations of 10, 30 or 100 μM) by themselves showed no effect.

Disadvantageously, loop samples obtained from animals treated with endogenous toxins show a loss of stiffness within that period, even though the contractile effect is similarly induced by PE, and this loss of stiffness is also referred to as a low response of blood vessels. This phenomenon is strong in the case of intact free toxin (E +). The compounds of the present invention (in concentrations of 10, 30 or 100 μM) can reverse the loss of stiffness, which would inhibit the hyporeactivity of blood vessels as preparations with or without endothelial compounds. Indicates that it can.

The effects of the compounds of the present invention are characterized in inhibiting EDRF production, while L-arginine, a natural nitric oxide precursor, enhances loss of stiffness in the form of preparations treated with endotoxins.

In some experiments, the compounds of the invention were injected into the bath 105 minutes after PE treatment, ie when the tissue was completely rigid. Under these conditions, the compounds of the present invention alone recovered the contraction completely therapeutically, significantly contributing to the low response of blood vessels to vasoconstrictor neurons in the spleen. In addition, the action of the compounds of the present invention may be further enhanced when mixed with blockers of cyclooxygenases such as aspirin and indomethacin. This was demonstrated by the following in vivo experiments.

After puncturing the cerebrospinal fluid of male Sprague Dawley rats (weight: 280-320 g), endogenous toxin (EDTX, E. coli leaf polysaccharide OIII: B ₄ ; 300 µg / kg / h) was continuously refluxed for 60 minutes. . This resulted in 40% of systemic hypotension (reduction of diastolic blood pressure), blood concentration and leukopenia accompanied by hypovascular response to stimulation of blood pressure-boosting agents. Vascular hyporesponse was measured by calculating the cumulative response curves for methoxamine (d ₁ -kinus) and calculating ED ₅₀ (50% of the effective dose). The ED ₅₀ value of methoxamine is 278 ± 34 μg / kg and 79 ± 9 μg / kg, respectively (n = 24) for rats and controls treated with EDTX. Each group consisted of 5 or 6 rats. The results are shown in the table below. After refluxing endotoxin lipopolysaccharide (300 μg / kg / h) for 60 minutes in cerebrospinal fluid-prone mice, hypotension was observed, as observed in human sepsis and endotoxin shock. Adversely affected the responsiveness of blood vessels to synergists. The low response of these vessels can be inhibited by the administration of EDRF blockers such as L-NMMA, L-NAME or L-NIO demonstrating in vivo experiments, in which case the degree of inhibition is dose dependent. However, the effect on blood pressure was not so significant. The combination of a block of cyclooxidases (eg, aspirin, indomethacin) and a block of EDRF has a very synergistic protective effect against hyporeactivity and blood pressure reduction caused by shock.

Thus, the present invention also relates to a therapeutic composition in which the compound is mixed with a block of cyclooxidase.

The activity that appears when two components are mixed is even more important than simply adding the activity of the two components.

Toxicity Test

Studies on the toxicity of the compounds of the present invention were conducted in rats and mice, but did not die at the maximum dose that could be administered.

[Pharmacodynamic Test]

A general pharmacokinetic test for the treatment of vaccination consists in dissolving or suspending the designated compound in serum when 10,500 mg / 1 h is administered by reflux when the designated compound of the present invention is used alone. The duration of treatment should be determined for each case in relation to the patient's sufficient recovery. When one compound according to the present invention is administered with a cyclooxygenase blocker, 10-100 mg of the designated compound according to the present invention is treated with 0.1-1 mg of indomethacin or 2-200 mg of aspirin or other cyclo It is mixed with an appropriate amount of blocking agent of oxygenase and administered by reflux for 1 hour.

Claims (4)

A therapeutic composition for treating a state of shock by reflux, characterized by containing an effective amount of a compound of the following formula as an essential ingredient. Wherein R ₁ and R ₄ are H, CH ₃ or C ₂ H ₅ , R ₂ is H or NO ₂ , and R ₃ is NHR ₄ , CH ₃ or C ₂ H ₅ . The composition of claim 1 containing 10-500 mg of said compound as an effective amount for reflux for 1 hour. A therapeutic composition for treating a spontaneous counterpart by reflux, characterized by containing an effective amount of a cyclooxygenase blocking agent selected from indomethacin and aspirin, and an effective amount of a mixture of a compound of the following formula: Wherein R ₁ and R ₄ are H, CH ₃ or C ₂ H ₅ , R ₂ is H or NO ₂ , and R ₃ is NHR ₄ , CH ₃ or C ₂ H ₅ . 4. The method of claim 3, wherein 10-100 mg of the compound, and 0.1-1 mg of indomethacin or 2-200 mg or other equivalent cyclooxygenase, as the effective amount of the mixture for reflux for 1 hour. Composition consisting of a blocker of.